First total synthesis of caerulomycin K: a case study on selective, multiple C–H functionalizations of pyridines

Caerulomycins, natural alkaloids with antimicrobial properties, have been previously synthesized starting with highly pre-functionalized building blocks or requiring many functional group manipulations. In this work, we report the first total synthesis of caerulomycin K, a diversely trifunctionalized pyridine readily assembled in three steps exploiting the recent advancements in the C–H activation of N-heterocycles.

Pyridines are ubiquitous in many natural products and drugs, oen with a wide selection of functionalities decorating these aromatic rings. 1,2While classical pyridine syntheses (e.g.Bohlmann-Rahtz reaction, Hantzsch condensation, etc.) allow the introduction of substituents in the nal ring, the functionalization of existing pyridines using C-H activation is usually a better option to avoid the de novo synthesis of complex pyridines. 3However, despite pyridines exhibiting a clear similarity to benzenes, they present distinct challenges when it comes to their C-H functionalization. 4,5As a result, relatively simple pyridines may require several steps to be synthesized, especially if the substituents around the aromatic ring are different in nature.][14][15][16][17][18][19][20][21] Yet, the installation of these functionalities via C-H activation is not straightforward since it requires several functional group interconversions (Scheme 1B).
Specically, the installation of the methoxy group can require four steps: formation of the N-oxide with an oxidant, nitration with concentrated H 2 SO 4 , nucleophilic aromatic substitution (S N Ar) with MeONa, and removal of the oxide with Ac 2 O. 18,19 The insertion of an ortho-pyridine group is usually more rapid but requires the use of Grignard reagents or prefunctionalized 2-bromopyridines. 15,16Finally, the insertion of the carbonyl group is achieved by oxidation of a methyl group whose installation has been obtained only with a halogen (Cl or Br) already placed in ortho-position. 18,21Given the recent advancements in selective C-H functionalizations of pyridines, 4,5 it would be expected that alternative strategies should now allow a faster synthesis of caerulomycins.Herein, we report our efforts to rapidly convert a cheap monosubstituted pyridine into caerulomycin K, a recently isolated alkaloid whose total synthesis has never been reported before.
Scheme 1 Structures and synthetic routes to caerulomycins.
Our investigation began with the design of a synthetic route that would furnish caerulomycin K in a few steps using two C-H activations, thus avoiding highly pre-functionalized starting materials.In an initial retrosynthetic approach, we imagined that the aldoxime group could be derived from a methyl group, as reported by Quéguiner and co-workers, thus leading to trifunctionalized pyridine I (Scheme 2A). 183][24] Salt III could then be obtained from 2-phenylpyridine 1 via two consecutive C-P bond formation reactions, in analogy with a rare example of a pyridyl bisphosphonium salt (Scheme 2B). 25,26his strategy would provide the desired product in 5 steps, whereas the ionic nature of most intermediates would reduce the need for column chromatography.Moreover, considering the wide versatility of ligand-coupling reactions, 25,26 III would be a strategic intermediate for the synthesis of libraries of trifunctionalized pyridines by simply changing the order and the nature of the added nucleophiles.In the laboratory, 1 was dissolved in dichloromethane and cooled down to −78 °C, before sequentially adding Tf 2 O, Ph 3 P, and DBU (Scheme 3).In agreement with McNally's work, 27 upon workup, 2 was easily precipitated out as a white powder from cold ether (88% isolated yield).Notably, the Ph 3 P addition occurs almost exclusively at the para-position (due to stereoelectronic reasons), thus no regioselectivity problems are encountered during this reaction. 28This was also conrmed by 31 P NMR, with only a sharp singlet observed at 23.01 ppm.Repeating the procedure using now 2 as the starting material, the reaction crude revealed two new signals of similar intensity at 23.55 ppm and 15.37 ppm.
These signals were respectively assigned to the para-and ortho-phosphine of bis-phosphonium bis-triate 3.However, the conversion was only modest by 31 P NMR, with signicant unreacted 2 and Ph 3 PO observed in the reaction mixture.The failure of the second C-P bond formation was attributed to a problematic N-activation since 2 should be less nucleophilic than 1 due to its cationic nature.This was conrmed using phosphonium 5, obtained in good yield from 3-phenylpyridine 4: moving away the phenyl ring from the ortho-to the metaposition improved the second C-P bond formation (5 less sterically encumbered than 2), yet not to a signicant extent due to electronic reasons.Indeed, bis-phosphonium 6 was found as a minor component in 31   Finally, attempts to use a more nucleophilic phosphine (i.e.(4-anisyl) 3 P) did not improve the C-P bond formation, and neither did the use of it as the rst installed phosphine (see ESI †).Indeed, the use of (4-anisyl) 3 P mainly resulted in the formation of the corresponding phosphine oxide, as expected for electron-rich phosphines.Given the problematic separation of salts 2 and 3 and the modest conversion observed in the second step, we decided to perform one C-P bond formation at a time.Treatment of 2 with MeONa in dichloromethane gave disubstituted pyridine 7 in 53% 1 H NMR yield (Scheme 5), although its isolation was complicated by co-eluting Ph 3 PO (the product, together with 1, of competitive proto-Before performing the second C-P bond formation on 7, the installation of a methyl group using 2 as a model compound was attempted. 3][34] However, the direct use of organolithium has been shown successful in a couple of cases (e.g.ArLi), hence we hoped the use of MeLi or MeMgBr would avoid extra steps. 27Unfortunately, treatment of 2 with these organometallics provided equimolar amounts of 2,4-diphenylpyridine 8 and Ph 2 P(O)Me (Scheme 5), the latter observable in the 1 H NMR spectrum (2.01 ppm, d, 2 J P-H = 13.2Hz, 3H, Me).This result highlights how, in contrast to alkoxides, the phenyl ring has a higher migration aptitude than a methyl group during the ligand-coupling of the phosphorane intermediate, 35,36 thus leading to 8 and Ph 2 PMe (then oxidized during the workup).An alternative approach to the use of phosphonium salts would be an ortho-halogenation followed by Negishi coupling with MeZnCl, in analogy with the reported synthesis of caerulomycin E. 18 These halogenations (Reissert-Henze reactions) require the use of N-oxides, easily made upon treatment of pyridines with an oxidant such as H 2 O 2 or mchloroperbenzoic acid (mCPBA). 37Initially, using 1-O as a model substrate, activation with Tf 2 O and bromination with tetra-nbutylammonium bromide (TBAB) was attempted, in analogy with the ortho-bromination of quinolines reported by Baran and co-workers (Scheme 6). 38However, no desired product was observed, but only a mixture of brominated pyridines, probably due to some Br 2 formed from the residual oxidant (mCPBA) still present in 1-O.In contrast to pyridines, the successful orthobromination observed by Baran for quinolines reects the lower loss in resonance stabilization typical of bicyclic aromatics (i.e.naphthalene vs. benzene).Chlorination of 1-O with POCl 3 gave better results (9 isolated in 55% yield), but the need for harsh conditions (neat POCl 3 reuxing at 106 °C) somehow defeated our original purpose for a short and mild synthesis, thus a completely different strategy was considered.
Minisci-type chemistry is an excellent method for orthofunctionalizations of pyridines, especially employing nucleophilic carbon-based radicals (ideal for the synthesis of caerulomycin K). 39,40 Moreover, starting with a 4-substituted pyridine would prevent regioselectivity issues (C2 vs. C6) typical of unsymmetrical starting materials.For the ortho-arylation of pyridines, Baran and others have shown how aryl boronic esters, in combination with AgNO 3 , Na 2 S 2 O 8 , and TFA, are excellent aryl radical precursors. 41,42To install a carbonyl group, Angeles, Yeung, and colleagues have used 1,3,5-trioxanes as an aldehyde equivalent in Minisci-type carbonylation of pyridines. 43Based on this precedent, a Minisci arylation of 4chloropyridine 10 was performed (Scheme 7).In this case, an excess of phenylboronic acid (1.5 equiv.) was needed to compensate for competitive protodeboronation, whereas a higher loading of AgNO 3 allowed the isolation of product 11 in 56% yield.A second Minisci reaction was then performed on this pyridine using 1,3,5-trioxane in the presence of (nBu 4 N) 2 -S 2 O 8 .A successful ortho-alkylation gave product 12 in 50% yield (a value in agreement with previous reports), [44][45][46][47] whereas a subsequent nucleophilic aromatic substitution allowed to access trifunctionalized pyridine 13 almost quantitatively.It has to be noted that starting from 4-methoxypyridine 14 would shorten the synthesis, but the electron-donating effect of the methoxy group will negatively affect both steps since Minisci reactions are based on the addition of nucleophilic radicals.The nal conversion of 13 into caerulomycin K was achieved in a one-pot procedure by treatment with HCl (to reveal the aldehyde functionality), followed by condensation with NH 2 OH.Importantly, 12 could be directly converted into caerulomycin K Scheme 5 Ligand-coupling reactions with phosphonium salt 2. 1 H NMR yield determined using CH 2 Br 2 as internal standard (in brackets, isolated yield).
without the need for isolation of 13, further simplifying the synthesis (route in green).Therefore, this three-step total synthesis (overall yield of 10%) represents the rst synthesis of caerulomycin K as well as a potential alternative to the synthesis of caerulomycins.
In conclusion, the rst total synthesis of caerulomycin K has been reported.Starting from monofunctionalized pyridines, the rst strategy looked at a double C-H activation by means of phosphonium chemistry.However, a poor conversion of the second C-P bond formation and a problematic ortho-methylation, including via halogenation, prompted the search for a better alternative.This was achieved by sequential Minisci ortho-arylation and ortho-alkylation, with the latter converted in one pot into the desired oxime.Compared to previously reported caerulomycin syntheses, this novel approach does not require highly pre-functionalized starting materials.
Scheme 2 Reactivity of bis-phosphonium salts and application in the planned retrosynthesis of caerulomycin K.The triflate anion is not reported for clarity.

Scheme 3
Scheme 3 Attempted bis-phosphonium salts synthesis.The triflate anion is not reported for clarity.